Neuroscience

Obesity is the main culprit in the worldwide avalanche of type 2 diabetes. But how excess weight drives insulin resistance, the condition that may lead to the disease, is only partly understood. Scientists at Joslin Diabetes Center now have uncovered a new way in which obesity wreaks its havoc, by altering the production of proteins that affect how other proteins are spliced together. Their finding, published in Cell Metabolism, may point toward novel targets for diabetes drugs.

Scientists in the lab of Mary-Elizabeth Patti, M.D., began by examining the levels of proteins in the livers of obese people, and finding decreases in number for certain proteins that regulate RNA splicing.

“When a gene is transcribed by the cell, it generates a piece of RNA,” explains Dr. Patti, who is also an Assistant Professor of Medicine at Harvard Medical School. “That piece of RNA can be split up in different ways, generating proteins that have different functions.”

“In the case of these proteins whose production drops in the livers of obese people, this process changes the function of other proteins that can cause excess fat to be made in the liver,” she adds. “That excess fat is known to be a major contributor to insulin resistance.”

Additionally, the researchers showed that these RNA splicing proteins are diminished in samples of muscle from obese people.

The investigators went on to examine a representative RNA-splicing protein called SFRS10 whose levels drop in muscle and liver both in obese people and in over-fed mice. Working in human cells and in mice, they demonstrated that SFRS10 helps to regulate a protein called LPIN1 that plays an important role in synthesizing fat. Among their results, mice in which they suppressed production of SFRS10 made more triglycerides, a type of fat circulating in the blood.

“More broadly, this work adds a novel insight into how obesity may induce insulin resistance and diabetes risk by changing critical functions of cells, including splicing,” says Dr. Patti. “This information should stimulate the search for other genes for which differences in splicing may contribute to risk for type 2 diabetes. Ultimately, we hope that modifying these pathways with nutritional or drug therapies could limit the adverse consequences of obesity.”

With its first comprehensive set of results published today, the Great Brain Experiment, a free mobile app run by neuroscientists at the Wellcome Trust Centre for Neuroimaging at UCL, uses ‘gamified’ neuroscience experiments to address scientific questions on a scale that would not be possible using traditional approaches. The app investigates memory, impulsivity, risk-taking and happiness. By playing the games, anyone can anonymously compare their abilities to the wider population and contribute to real scientific research. More than 60,000 people have taken part so far.

The results, published in the journal PLOS ONE, demonstrate that mobile games can be used to reliably conduct research in psychology and neuroscience, reproducing well-known findings from laboratory studies. The small size of standard laboratory studies means they can be limited in their ability to investigate variability in the population at large. With data sent in from many thousands of participants, the scientists at UCL can now investigate how factors such as age and education affect cognitive functions. This new way of doing science enables questions to be addressed which would not previously have been practical.

Writing in the journal PLOS ONE, the researchers explained: “Smartphone users represent a participant pool far larger and more diverse than could ever be studied in the laboratory. By 2015, there will be an estimated two billion smartphone users worldwide. In time, data from simple apps could be combined with medical, genetic or lifestyle information to provide a novel tool for risk prediction and health monitoring.”

The Great Brain Experiment was funded by the Wellcome Trust and first released as part of last year’s Brain Awareness Week. Building on its initial success, the researchers have recently added four new games, including a “coconut shy” which tests people’s ability to perform under pressure. From this, the scientists hope to better understand how people make accurate movements in difficult situations. Going forward, they are calling on the public to download the app and throw coconuts to help science.

Rick Adams, a developer of The Great Brain Experiment based at the Wellcome Trust Centre for Neuroimaging at UCL, said: “The initial aim was simply to make the public more aware of cognitive neuroscience experiments, and how they are conducted. However, with such large numbers of people downloading the app and submitting their results, it rapidly became clear that there was the potential for studying task performance at an unprecedented scale.”

Harriet Brown, a researcher at the Wellcome Trust Centre for Neuroimaging at UCL, said: “It is hoped that carefully measuring performance on a range of tasks may give rise to a better understanding of common mechanisms that underlie performance on these different tasks. Through better understanding of these common mechanisms, we may be able to characterise how they are altered in neurological and psychiatric disease.”

Research from the University of Copenhagen is shedding new light on the brain’s complicated barrier tissue. The blood-brain barrier is an effective barrier which protects the brain, but which at the same time makes it difficult to treat diseases such as Alzheimer’s. In an in vitro blood-brain barrier, researchers can recreate the brain’s transport processes for the benefit of the development of new pharmaceuticals for the brain. The new research findings are published in the AAPS Journal.

Ninety-five per cent of all tested pharmacological agents for treating brain disorders fail, because they cannot cross the blood-brain barrier. It is therefore important to find a possible method for transporting drugs past the brain’s efficient outpost and fervent protector.

Researchers at the Department of Pharmacy at the University of Copenhagen have recreated the complex blood-brain barrier in a laboratory model, which is based on cells from animals. In a new study, the researchers have studied the obstreperous bouncer proteins in the barrier tissue. The proteins protect the brain, but also prevent the treatment of brain diseases:

"The blood-brain barrier is chemically tight because the cells contain transporter proteins which make sure that substances entering the cells are thrown straight back out into the bloodstream again. We have shown that the barrier which we have created in the laboratory contains the same bouncer proteins – and that they behave in the same way as in a ‘real’ brain. This is important, because the model can be used to test drive the difficult way into the brain. Complex phenomena – which we have so far only been able to study in live animals –can now be investigated in simple laboratory experiments using cultivated cells," says postdoc Hans Christian Cederberg Helms from the Department of Pharmacy.

The research team has shown that the transporter proteins P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 1 are active in the artificially created barrier tissue. The proteins pump pharmacological agents from the ‘brain side’ to the ‘blood side’ in the same way as in the human blood-brain barrier.

Collaboration finds a way

The new findings have resulted from collaboration with industrial scientists from the pharmaceutical company H. Lundbeck A/S. “It is important to the treatment of brain diseases such as Alzheimer’s that we find a way of circumventing the brain’s effective defence. The university and industry must work together to overcome the fundamental challenges inherent in developing pharmaceuticals for the future,” says Lassina Badolo, Principal Scientist with H. Lundbeck A/S and an expert on the absorption of medicines in the body.

Associate Professor Birger Brodin adds: “We have shown that the models have the same bouncer proteins as the ones found in the intact barrier. We are now in the process of studying the proteins in the blood-brain barrier that accept pharmacological agents instead of throwing them out. If we can combine a beneficial substance which the brain needs with a so-called ‘absorber protein’, we will in the long term be able to smuggle pharmacological agents across the blood-brain barrier.”

Birger Brodin heads the Drug Transporters in ADME research group which is responsible for the in vitro blood-brain barrier.

The area of the brain that plays a primary role in emotional learning and the acquisition of fear – the amygdala – may hold the key to who is most vulnerable to post-traumatic stress disorder.

Researchers at the University of Washington, Boston Children’s Hospital, Harvard Medical School and Boston University collaborated on a unique opportunity to study whether patterns of brain activity predict teenagers’ response to a terrorist attack.

The team had already performed brain scans on Boston-area adolescents for a study on childhood trauma. Then in April 2013 two bombs went off at the finish line of the Boston Marathon, killing three people and injuring hundreds more. Even people who were nowhere near the bombing reported distress about the attack and the days-long manhunt for the suspects.

So, one month after the attack, Katie McLaughlin, then at Boston Children’s Hospital and Harvard Medical School and now an assistant professor of psychology at the UW; co-author Margaret Sheridan, of Boston Children’s Hospital and Harvard Medical School; and their fellow researchers sent online surveys to teenagers who had previously participated in studies to assess PTSD symptoms related to the attack.

By using functional Magnetic Resonance Imaging scans from before the attack and survey data from after, the researchers found that heightened amygdala reaction to negative emotional stimuli was a risk factor for later developing symptoms of PTSD.

The research study was published July 3 in the journal Depression and Anxiety.

“The amygdala responds to both negative and positive stimuli, but it’s particularly attuned to identifying potential threats in the environment,” said McLaughlin, the study’s first author. “In the current study of adolescents the more their amygdala responded to negative images, the more likely they were to have symptoms of PTSD following the terrorist attacks.”

The brain scans were conducted during the year prior to the bombing. At that time, the teens were evaluated for their responses to emotional stimuli by viewing neutral and negative images. Neutral images included items such as a chair or button. Negative images showed people who were sad, fighting or threatening someone else. Participants rated the degree of emotion they felt while looking at each image. The MRIs measured whether blood flow increased to the amygdala and the hippocampus when viewing negative images as compared to neutral images.

In the follow-up survey the teens were asked whether they were at the finish line during the bombing, how much media exposure they had after the attack, whether they were part of the lockdown at home or school while authorities searched for the suspects, and how their parents responded to the incident. They also were asked about specific PTSD symptoms, such as how often they had trouble concentrating and whether they kept thinking about the bombing when they tried not to.

Researchers found a significant association between amygdala activation while viewing negative images and whether the teens developed PTSD symptoms after the bombing.

McLaughlin said a number of previous studies have shown that people with PTSD had heightened amygdala responses to negative emotions, but researchers didn’t know whether that came before or after the trauma.

“It’s often really difficult to collect neurobiological markers before a traumatic event has occurred,” she said. By scanning the adolescents’ brains before the bombing, she and her fellow researchers were able to show that “amygdala reactivity before a traumatic event predicts your response to that traumatic event.”

While two-thirds of Americans will be exposed to some kind of traumatic event during their lifetime, most, fortunately, will not develop PTSD.

“The more we understand the underlying neurobiological systems that shape reactions to traumatic events, the closer we move to understanding a person’s increased vulnerability to them,” McLaughlin said. “That could help us develop early interventions to help people who might develop PTSD later.”

A team of researchers at the Neuroscience Institute at Georgia State University has discovered that hidden differences in the properties of neural circuits can account for whether animals are behaviorally susceptible to brain injury. These results could have implications for the treatment of brain trauma.

People vary in their responses to stroke and trauma, which impedes the ability of physicians to predict patient outcomes. Damage to the brain and nervous system can lead to severe disabilities, including epilepsy and cognitive impairment.

If doctors could predict outcomes with greater accuracy, patients might benefit from more tailored treatments. Unfortunately, the complexity of the human brain hinders efforts to explain why similar brain damage can affect each person differently.

The researchers used a unique research animal, a sea slug called Tritonia diomedea, to study this question. This animal was used because unlike humans, it has a small number of neurons and its behavior is simple. Despite this simplicity, the animals varied in how neurons were connected.

Under normal conditions, this variability did not matter to the animals’ behavior, but when a major pathway in the brain was severed, some of the animals showed little behavioral deficit, while others could not produce the behavior being studied. Remarkably, the researchers could artificially rewire the neural circuit using computer-generated connections and make animals susceptible or invulnerable to the injury.

“This study is important in light of the current Obama BRAIN initiative, which seeks to map all of the connections in the human brain,” said Georgia State professor, Paul Katz, who led the research project. “it shows that even in a simple brain, small differences that have no effect under normal conditions, have major implications when the nervous system is challenged by injury or trauma.”

Results of this study were published in the most recent edition of the journal eLife. The lead author on the study, Dr. Akira Sakurai, made this discovery in the course of doing basic research. He was assisted by Ph.D. student Arianna Tamvacakis from Dr. Katz’s lab.

A new study from the Gladstone Institutes has revealed a way to alleviate the learning and memory deficits caused by apoE4, the most important genetic risk factor for Alzheimer’s disease, improving cognition to normal levels in aged mice.

In the study, which was conducted in collaboration with researchers at UC San Francisco and published today in the Journal of Neuroscience, scientists transplanted inhibitory neuron progenitors—early-stage brain cells that have the capacity to develop into mature inhibitory neurons—into two mouse models of Alzheimer’s disease, apoE4 or apoE4 with accumulation of amyloid beta, another major contributor to Alzheimer’s. The transplants helped to replenish the brain by replacing cells lost due to apoE4, regulating brain activity and improving learning and memory abilities.

“This is the first time transplantation of inhibitory neuron progenitors has been used in aged Alzheimer’s disease models,” said first author Leslie Tong, a graduate student at the Gladstone Institutes and UCSF. “Working with older animals can be challenging from a technical standpoint, and it was amazing to see that the cells not only survived but affected activity and behavior.”

The success of the treatment in older mice, which corresponded to late adulthood in humans, is particularly important, as this would be the age that would be targeted were this method ever to be used therapeutically in people.

“This is a very important proof of concept study,” said senior author Yadong Huang, MD, PhD, an associate investigator at Gladstone Institutes and associate professor of neurology and pathology at UCSF. “The fact that we see a functional integration of these cells into the hippocampal circuitry and a complete rescue of learning and memory deficits in an aged model of Alzheimer’s disease is very exciting.” 

A balance of excitatory and inhibitory activity in the brain is essential for normal function. However, in the apoE4 model of Alzheimer’s disease—a genetic risk factor that is carried by approximately 25% of the population and is involved in 60-75% of all Alzheimer’s cases—this balance gets disrupted due to a decline in inhibitory regulator cells that are essential in maintaining normal brain activity. The hippocampus, an important memory center in the brain, is particularly affected by this loss of inhibitory neurons, resulting in an increase in network activation that is thought to contribute to the learning and memory deficits characteristic of Alzheimer’s disease. The accumulation of amyloid beta in the brain has also been linked to this imbalance between excitatory and inhibitory activity in the brain.

In the current study, the researchers hoped that by grafting inhibitory neuron progenitors into the hippocampus of aged apoE4 mice, they would be able to combat these effects, replacing the lost cells and restoring normal function to the area. Remarkably, these new inhibitory neurons survived in the hippocampus, enhancing inhibitory signaling and rescuing impairments in learning and memory.

In addition, when these inhibitory progenitor cells were transplanted into apoE4 mice with an accumulation of amyloid beta, prior deficits were alleviated. However, the new inhibitory neurons did not affect amyloid beta levels, suggesting that the cognitive enhancement did not occur as a result of amyloid clearance, and amyloid did not impair the integration of the transplant.

According to Dr. Huang, the potential implications for these findings extend beyond the current methods used. “Stem cell therapy in humans is still a long way off. However, this study tells us that if there is any way we can enhance inhibitory neuron function in the hippocampus, like through the development of small molecule compounds, it may be beneficial for Alzheimer disease patients.”

The inability to ignore irrelevant stimuli underlies the impaired working memory and cognition often experienced by individuals diagnosed with schizophrenia, reports a new study in the current issue of Biological Psychiatry.

Our brains are usually good at focusing on the information that we are trying to learn and filtering out the “noise” or thoughts that aren’t relevant. However, memory impairment in schizophrenia may be related in part to a problem with this filtering process, which Dr. Teal Eich at Columbia University and her colleagues studied.

“Our assumption was that understanding the impairments in the component processes of working memory – the ability to hold and manipulate information in the mind – among patients with schizophrenia could be fundamental to understanding not only cognitive function in the disorder, which is widespread and has debilitating consequences, but also the disorder itself,” Eich explained.

The researchers recruited patients with schizophrenia and a control group of healthy volunteers to complete an item recognition task in the laboratory while undergoing a functional magnetic resonance imaging scan. In particular, they focused on analyzing potential activation differences in the ventro-lateral prefrontal cortex (VLPFC), a region of the brain implicated in working memory.

The design of the task allowed for the assessment of the various components of working memory: 1) maintaining the memory itself, 2) inhibiting or ignoring irrelevant information, and 3) during memory retrieval, controlling the interference of irrelevant information.

While simply maintaining the memory, both groups showed a similar degree of activation in the VLPFC. During the inhibition phase, VLPFC activity is expected to decrease, which was indeed observed in the healthy group, but not in the patients. Finally, during interference control, patients performed worse and showed increased VLPFC activation compared to the healthy volunteers. Overall, the patients showed altered VLPFC functioning and significant impairments in their ability to control working memory.

“Our findings show that these patients have a specific deficit in inhibiting information in working memory, leading to impaired distinctions between relevant and irrelevant thoughts,” said Eich. “This result may provide valuable insights into the potential brain mechanisms underlying the reasons why these affected individuals are unable to control or put out of mind certain thoughts or ideas.”

This study adds to a growing literature suggesting that cognitive functions require both the activation of one set of regions and the inhibition of others. The failure to suppress activation may be just as disruptive to cortical functions as deficits in cortical activation.

Many years ago, the pioneering scientist Patricia Goldman-Rakic and her colleagues showed that the inhibition of regional prefrontal cortical activity was dependent upon the integrity of the GABA (gamma-aminobutyric acid) system in the brain, a chemical system with abnormalities associated with schizophrenia.

“We need to determine whether the cortical inhibitory deficits described in this study can be attributed to particular brain chemical signaling abnormalities,” said Dr. John Krystal, Editor of Biological Psychiatry. “If so, this type of study could be used to guide therapeutic strategies to enhance working memory function.”

Older people are nearly twice as likely as their younger counterparts to have their memory and cognitive processes impaired by environmental distractions (such as irrelevant speech or written words presented along with target stimuli), according to a new study from psychologists at Rice University and Johns Hopkins University School of Medicine. Whereas other studies had found that older adults are distracted by memories of prior similar events, this was the first study to convincingly demonstrate across several tasks an impairment from environmental distractions.

“Cognitive Declines in Healthy Aging: Evidence from Multiple Aspects of Interference Resolution” appeared in a recent edition of Psychology and Aging. The study supported previous research that showed memory accuracy and the speed of cognitive processing declines with age. It also revealed that older people were at least twice as likely as younger to have irrelevant memories intrude during memory recall and also showed twice as much slowing in cognitive processing in the presence of distracting information in the environment.

The study included 102 people between the ages of 18 and 32 (average age of 21) and 60 people between the ages of 64 and 82 (average age of 71) who participated in a series of memory and cognitive tasks.

For example, when the participants were tested on remembering lists of words, individuals in the young test group remembered words on the list with an average accuracy of 81 percent; in comparison, the old test group’s accuracy was only 67 percent. When irrelevant words were introduced that were to be ignored, the young test group’s accuracy dropped to 74 percent, but the accuracy of the old test group’s performance dropped to 46 percent.

“Almost any type of memory test administered reveals a decline in memory from the age of 25 on,” said Randi Martin, the Elma W. Schneider Professor of Psychology at Rice and the study’s co-author. “However, this is the first study to convincingly demonstrate the impact of environmental interference on processing having a greater impact on older than younger adults.”

Martin hopes that the research will encourage further research of how the brain is affected by environmental distractions.

“From our perspective of studying neuroplasticity (the brain’s ability to reorganize itself after traumatic injury or neurological disorders) and testing patients with brain damage, this research is very important,” Martin said. “The tests used in this study are important tools in determining how the brain is affected by environmental interference, which is critical information in treating neurological disorders, including stroke and traumatic brain injuries.”

Up to 70% of Parkinson’s disease (PD) patients experience sleep problems that negatively impact their quality of life. Some patients have disturbed sleep/wake patterns such as difficulty falling asleep or staying asleep, while other patients may be subject to sudden and involuntary daytime sleep “attacks.” In the extreme, PD patients may exhibit REM-sleep behavior disorder (RBD), characterized by vivid, violent dreams or dream re-enactment, even before motor symptoms appear. A review in the Journal of Parkinson’s Disease discusses the underlying causes of sleep problems in PD, as well as medications, disease pathology, and comorbidities, and describes the most appropriate diagnostic tools and treatment options.

Sleep problems in PD patients can have wide-ranging adverse effects and can worsen in later stages of the disease. Sleepiness socially isolates patients and excessive sleepiness can put patients at risk of falls or injury, and can mean patients must give up driving. Sleepiness can impair cognition and concentration, exacerbate depression, and interfere with employment. Wakefulness at night impairs daytime wakefulness and may also cause mood instabilities and can exhaust caregivers.

“Diagnosis and effective treatment and management of these problems are essential for improving the quality of life and reducing institutionalization of these patients,” says lead author Wiebke Schrempf, MD, Technische Universität Dresden, Faculty of Medicine Carl Gustav Carus, Department of Neurology, Division of Neurodegenerative Diseases, Dresden, Germany.

Dr. Schrempf and colleagues describe some of the complexities associated with treating sleep problems in PD patients, such as the worsening of sleep problems by dopaminergic medications used to treat motor symptoms. Lower doses of levodopa or dopamine agonists are able to improve sleep quality partly by reducing motor symptoms such as nighttime hypokinesia (decreased body movement), dyskinesia (abnormal voluntary movements), or tremor (involuntary shaking), which interfere with normal sleep. However, the same medications may also cause excessive daytime sleepiness. The report describes how changing medication, dose, duration of treatment, or timing of administration can improve outcomes.

The presence of other conditions common in PD patients such as depression, dementia, hallucinations, and psychosis may interfere with sleep. Unfortunately, some antidepressants can also impair sleep.

Sleep problems may also be harbingers of future neurodegenerative disease. Patients with RBD exhibit intermittent loss of normal muscle relaxation during REM sleep and engage in dream enactment behavior during which they may shout, laugh, or exhibit movements like kicking and boxing. “RBD seems to be a good clinical predictor of emerging neurodegenerative diseases with a high specificity and low sensitivity, whereas other early clinical features of PD, such as olfactory dysfunction and constipation, are less specific,” says Dr. Schrempf. “These early clues may help identify PD patients before motor symptoms appear, when disease-modifying therapies may be most beneficial.”

PD is the second most common neurodegenerative disorder in the United States, affecting approximately one million Americans and five million people worldwide. Its prevalence is projected to double by 2030. The most characteristic symptoms are movement-related, such as involuntary shaking and muscle stiffness. Non-motor symptoms, such as worsening depression, cognition, and anxiety, olfactory dysfunction, and sleep disturbances, can appear prior to the onset of motor symptoms.

Amidst the astounding complexity of the billions of nerve cells and trillions of synaptic connections in the brain, how do nerve cells decide how far to grow or how many connections to build? How do they coordinate these events within the developing brain?

In a new study, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed new light on these complex processes, showing that a particular protein plays a far more sophisticated role in neuron development than previously thought.

The study, published in the journal PLOS Genetics, focuses on the large, intracellular signaling protein RPM-1 that is expressed in the nervous system. TSRI Assistant Professor Brock Grill and his team show the surprising degree to which RPM-1 harnesses sophisticated mechanisms to regulate neuron development.

Specifically, the research sheds light on the role of RPM-1 in the development of axons or nerve fibers—the elongated projections of nerve cells that transmit electrical impulses away from the neuron via synapses. Some axons are quite long; in the sciatic nerve, axons run from the base of the spine to the big toe.

“Collectively, our recent work offers significant evidence that RPM-1 coordinates how long an axon grows with construction of synaptic connections,” said Grill. “Understanding how these two developmental processes are coordinated at the molecular level is extremely challenging. We’ve now made significant progress.”

Putting Together the Pieces

The study describes how RPM-1 regulates the activity of a single protein known as DLK-1, a protein that regulates neuron development and plays an essential role in axon regeneration. RPM-1 uses PPM-2, an enzyme that removes a phosphate group from a protein thereby altering its function, in combination with intrinsic ubiquitin ligase activity to directly inhibit DLK-1.

“Studies on RPM-1 have been critical to understanding how this conserved family of proteins works,” said Scott T. Baker, the first author of the study and a member of Grill’s research team. “Because RPM-1 plays multiple roles during neuronal development, you wouldn’t want to interfere with it. But exploring the role of PPM-2 in controlling DLK-1 and axon regeneration could be worthwhile—and could have implications in neurodegenerative diseases.”

The Grill lab has also explored other aspects of how RPM-1 regulates neuron development. A related study, also published in PLOS Genetics, shows that RPM-1 functions as a part of a novel pathway to control β-catenin activity—this is the first evidence that RPM-1 works in connection with extracellular signals, such as a family of protein growth factors known as Wnts, and is part of larger signaling networks that regulate development. A paper in the journal Neural Development shows that RPM-1 is localized at both the synapse and the mature axon tip, evidence that RPM-1 is positioned to potentially coordinate the construction of synapses with regulation of axon extension and termination.

A recent study shows that assimilation of L2 vowels to L1 phonemes governs language learning in adulthood; researchers urge development of novel methods of second language teaching.

The behavioral and neural evidence of the study was found by researchers at Aalto University in Finland and at the University of Salento in Italy. The study was the first one to identify the neural mechanisms underlying the learning of L2 sounds (second language) in adulthood. Overall, this and earlier studies support the hypothesis that students in a foreign language classroom should particularly benefit from learning environments where they receive a focused amount of high-quality input from L2 native teachers, use pervasively the L2 to achieve functional and communicative goals, and receive intensive training (including the use of multi-medial systems) in the perception and production of L2 sounds in order to reactivate neuroplasticity of auditory cortex.

Learning in adulthood the sounds of a second language L2 means assimilating them to the phonemes of the native language L1.

In the study, two samples of Italian students, attending first year and fifth year classes of an English Language curriculum were invited to the behavioral and electroencephalography (EEG) lab. Dr. Brattico, senior author of the study from Aalto University, explains: “The discrimination skills were measured by crossing two methodologies: on one hand, perception tests in which the students listened to couples of English sounds that I synthesized and had to judge how similar or different they were, and on the other hand, EEG recordings with 64 electrode cap, while the students were presented with the same pairs of sounds and watched a silenced movie.”

The EEG recordings were used to extract the auditory event-related potential, namely the succession of neural events necessary to the processing and representation of sound, originating from the auditory cortex.
“When we hear linguistic sounds that are part of our native tongue, in a few milliseconds the brain is able to decipher the acoustic signal, extract the peculiar characteristics of each sound and produce a mental representation of it: thus we are able to discern one sound from another and assemble first the syllables, then the words and so on”, adds the first author, Professor Grimaldi, University of Salento.

“We compared the neural responses of the auditory cortex of the two groups of university students with one another and with a control group with a low level of education (third year of junior secondary school)”, explains Grimaldi. “We started with this hypothesis: if during the academic studies the students had developed new perceptual abilities we would have found different neural responses for the three groups”. The results did not confirm the hypothesis, but instead showed that neutrally, the L2 sounds were assimilated to L1 phonemes in all the groups.

Grimaldi adds: “Let us consider, for example, what happens when we watch a movie or listen to a song in a language that we do not know: we are able to perceive acoustic differences, but we cannot `extract´ the words from the acoustic stream and accede to their meaning. This is what happened for our groups of students”. Previous behavioral studies that observed L2 learners who had different native languages in an educational context (German, Finnish, Japanese, Turkish and other English learning students) never produced results favorable for the teachers. “This study specifies confirms and extends such results, proving by means of neurophysiological data that the quantity and quality of the stimuli received by university students are not enough to form long-term traces of L2 sounds in the auditory cortex”, confirms Brattico.

The results were published online in Frontiers in Human Neuroscience.

A neuroscientist at Rutgers University-Newark says the human brain operates much the same whether active or at rest – a finding that could provide a better understanding of schizophrenia, bipolar disorder and other serious mental health conditions that afflict an estimated 13.6 million Americans.

In newly published research in the journal Neuron, Michael Cole, an assistant professor at the Center for Molecular and Behavioral Neuroscience, determined that the underlying brain architecture of a person at rest is basically the same as that of a person performing a variety of tasks.

This is important to the study of mental illness because it is easier to analyze a brain at rest, says Cole, who made the discovery using functional magnetic resonance imaging (fMRI). 

“We can now observe people relaxing in the scanner and be confident that what we see is there all the time,” says Cole, who initially feared his team might find that the brain reorganizes itself for every task. “If that had been the case, we would have had less hope that we could understand mental illness in our lifetime.”

Instead, Cole says, scientists can now make their search for causes of mental illness more focused – and he suggests at least one target of opportunity. The prefrontal cortex is a portion of the brain involved in high level thinking, as well as remembering what a person’s goal is and the task being performed.

Cole says it would be useful to explore whether connectivity between the prefrontal cortex and other areas of the brain is altered – while the brain is at rest – in people with severe mental illness. “And then we can finally say something fundamental,” he predicts, “about what’s different about the brain’s functional network in schizophrenia and other conditions.”

Those differences, in turn, could explain certain symptoms. For instance, what if a patient has visual hallucinations because poor connectivity between the prefrontal cortex and the portion of the brain that governs sight causes the hallucinations to override what the eyes actually see? Cole suggests that’s just one of the questions that analysis of the brain at rest might help to answer. Others include a person’s debilitating beliefs, such as overly negative self-assessment when depressed.

Opportunities to find better ways to improve patients’ lives might then follow. Cole notes that current medications for severe mental illness, when they help at all, typically do not relieve cognitive symptoms. It is possible the drugs will reduce hallucinations or depressing thoughts, but patients continue to have difficulty concentrating on the task at hand, and often find it hard to find or hold a job. Cole says that even solving that one issue would be a major step forward – and he hopes his new work has helped advance science toward achieving this goal.

A drug used to treat Parkinson’s disease could also help people with phobias or post-traumatic stress disorder (PTSD). Scientists of the Translational Neurosciences (FTN) Research Center at Johannes Gutenberg University Mainz (JGU) are currently exploring the effects of psychotherapy to extinguish fears in combination with L-dopa. This drug does not only help movement disorders, but might also be used to override negative memories.

Professor Raffael Kalisch, head of the Neuroimaging Center (NIC) of the JGU Translational Neurosciences Research Center, and his collaborators at the University of Innsbruck are conducting research in mice and in humans into the psychological and neurobiological mechanisms of anxiety and fear. “Fear reactions are essential to health and survival, but the memories of angst-inducing situations may cause long-term anxiety or phobias,” explained Kalisch. In psychotherapy, the ’fear extinction’ method is used in exposing people to a threat but without the adverse consequences. Latest research has proven that extinguishing fear also predicts mental health after trauma, suggesting extinction may be an important resilience mechanism.

Fear extinction involves a person being presented with a neutral stimulus, such as a circle on a screen, together with a painful sensation. Soon the person predicts pain in response to the circle on the screen and fear becomes conditioned. Then the person is shown the circle again, but this time without the painful stimulus, so that the person can disassociate the two factors. A person who is afraid of spiders, for example, will in psychotherapy be confronted with spiders in a way that reassures them that the spider is harmless.

In another research program, Belgian scientists tested the ability to extinguish fear in soldiers later deployed to a war zone and found differences in the soldiers’ resilience to traumatic memories. Some experienced post-traumatic stress symptoms following their deployment, whereas those who were able to extinguish fear in the laboratory maintained a good state of mental health. “If you are mentally flexible enough to change the associations that your mind has created, you might be better able to avoid lasting damage,” explained Kalisch. In cooperation with other scientists, Kalisch has found first evidence that this process of changing negative associations might involve the brain’s systems for reward and pleasure and depend on release of the neurotransmitter dopamine that helps control them.

However, even after successful extinction, old fear associations can return under other stressful circumstances. This might involve the development of PTSD or a relapse after successful psychotherapy. Kalisch has found that L-dopa, a drug to treat Parkinson’s disease, can prevent this effect and could therefore possibly be used to prevent relapse in treated PTSD or phobia patients. L-dopa is taken up by the brain and transformed into dopamine that not only controls the brain’s reward and pleasure centers and helps regulate movement, but also affects memory formation. The person receiving L-dopa after extinction will thus create a stronger secondary positive memory of the extinction experience and will thus be able to more easily replace the negative memory. This raises new questions about the role of primary fear memories and secondary prevention by L-dopa. “We would like to be able to enhance the long-term effects of psychotherapy by combining it with L-dopa,” said Professor Raffael Kalisch. To this end, he is about to start a clinical study of people with a spider phobia to determine the effects of L-dopa on therapy outcome. “Manipulating the dopamine system in the brain is a promising avenue to boost primary and secondary preventive strategies based on the extinction procedure,” he continued.

Publication:

Raczka, K. A. et al. (2011), Empirical support for an involvement of the mesostriatal dopamine system in human fear extinction, Translational Psychiatry 1:e12

Haaker, J. et al. (2013), Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear, PNAS Plus - Biological Sciences - Psychological and Cognitive Sciences 110 (26): E2428-36

Scientists have identified a set of 10 proteins in the blood which can predict the onset of Alzheimer’s, marking a significant step towards developing a blood test for the disease. The study, led by King’s College London and UK proteomics company, Proteome Sciences plc,analysed over 1,000 individuals and is the largest of its kind to date.

There are currently no effective long-lasting drug treatments for Alzheimer’s, and it is believed that many new clinical trials fail because drugs are given too late in the disease process. A blood test could be used to identify patients in the early stages of memory loss for clinical trials to find drugs to halt the progression of the disease.

The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, is the result of an international collaboration led by King’s College London and Proteome Sciences plc, funded by Alzheimer’s Research UK, the UK Medical Research Council, the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre and Proteome Sciences.

The researchers used data from three international studies. Blood samples from a total of 1,148 individuals (476 with Alzheimer’s disease; 220 with ‘Mild Cognitive Impairment’ (MCI) and 452 elderly controls without dementia) were analysed for 26 proteins previously shown to be associated with Alzheimer’s disease. A sub-group of 476 individuals across all three groups also had an MRI brain scan.  

Researchers identified 16 of these 26 proteins to be strongly associated with brain shrinkage in either MCI or Alzheimer’s. They then ran a second series of tests to establish which of these proteins could predict the progression from MCI to Alzheimer’s. They identified a combination of 10 proteins capable of predicting whether individuals with MCI would develop Alzheimer’s disease within a year, with an accuracy of 87 percent.

Dr Abdul Hye, lead author of the study from the Institute of Psychiatry at King’s College London, said: “Memory problems are very common, but the challenge is identifying who is likely to develop dementia. There are thousands of proteins in the blood, and this study is the culmination of many years’ work identifying which ones are clinically relevant. We now have a set of 10 proteins that can predict whether someone with early symptoms of memory loss, or mild cognitive impairment, will develop Alzheimer’s disease within a year, with a high level of accuracy.”

Professor Simon Lovestone, senior author of the study from the University of Oxford, who led the work whilst at King’s, said: “Alzheimer’s begins to affect the brain many years before patients are diagnosed with the disease. Many of our drug trials fail because by the time patients are given the drugs, the brain has already been too severely affected. A simple blood test could help us identify patients at a much earlier stage to take part in new trials and hopefully develop treatments which could prevent the progression of the disease. The next step will be to validate our findings in further sample sets, to see if we can improve accuracy and reduce the risk of misdiagnosis, and to develop a reliable test suitable to be used by doctors.”

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, said: “As the onset of Alzheimer’s is often slow and subtle, a blood test to identify those at high risk of the disease at an early stage would be of real value. Detecting the first signs of Alzheimer’s could improve clinical trials for new treatments and help those already concerned about their memory, but we’re not currently in a position to use such a test to screen the general population.

“With an ageing population, and age the biggest risk factor for Alzheimer’s, we are expecting rising numbers of people to be affected over the coming years. It’s important to develop new ways to intervene early in the disease to help people maintain their quality of life for as long as possible.”

Dr Ian Pike, co-author of the paper from Proteome Sciences, said: “By linking the best British academic and commercial research, this landmark study in Alzheimer’s disease is a major advance in the development of a simple blood test to identify the disease before clinical symptoms appear. This is the window that will offer the best chance of successful treatment. Equally important, a blood test will be considerably easier and less expensive than using brain imaging or cerebrospinal spinal fluid.

“We are in the process of selecting commercial partners to combine the protein biomarkers in a blood test for the global market, a key step forward to deliver effective and early treatment for this crippling disease.”

Alzheimer’s disease is the most common form of dementia. Globally, it is estimated that 135 million people will have dementia by 2050. In 2010, the annual global cost of dementia was estimated at$604 billion. MCI includes problems with day-to-day memory, language and attention,and can be an early sign of dementia, or a symptom of stress or anxiety. Approximately 10% of people diagnosed with MCI develop dementia within a year but apart from regular assessments to measure memory decline, there is currently no accurate way of predicting who will, or won’t, develop dementia.

Previous studies have also shown that PET brain scans and plasma in lumbar fluid can be used to predict the onset of dementia from MCI. However, PET imaging is highly expensive and lumbar punctures invasive.

The protein that is mutated in Huntington’s disease is critical for wiring the brain in early life, according to a new Duke University study.

(Image caption: The protein associated with Huntington’s disease, Htt, is critical in early brain development. Brains of 5-week-old mice whose Htt was deleted show signs of cellular stress — reactive astrocytes (green) and microglia (white and red) and faulty connections — in brain circuits that have already been linked to the disease. Credit: Spencer McKinstry)

Huntington’s disease is a progressive neurodegenerative disorder that causes a wide variety of symptoms, such as uncontrolled movements, inability to focus or remember, depression and aggression. By the time these symptoms appear, usually in middle age, the disease has already ravaged the brain.

The new findings, published July 9 in the Journal of Neuroscience, add to growing evidence that Huntington’s and other neurodegenerative disorders, such as Alzheimer’s disease, may take root during development, said lead author Cagla Eroglu, an assistant professor of cell biology in the Duke University Medical School, and member of the Duke Institute for Brain Sciences.

“The study is exciting because it means that, if we understand what these developmental errors are, we may be able to interfere with the first stage of the disease, before it shows itself,” Eroglu said.

Several years ago, Eroglu and her team were looking for molecular players involved in the formation of new connections, or synapses, in early brain development in mice when their studies unexpectedly hit on the huntingtin (Htt) protein, which is present throughout the body and which forms clumps in the brain cells of people with Huntington’s disease.

“(Htt) had been implicated in certain cellular functions and synaptic dysfunction in Huntington’s, but the possibility that Htt is playing a direct role in synapse formation was not explored,” Eroglu said.

To understand the protein’s role as synapses form, the scientists created mice in which Htt is deleted only in the cortex, a part of the brain that is implicated in the disease and that controls perception, memory and thought.

At three weeks of age (roughly similar to the first two years of human life), a time when a mouse begins to take in its surroundings through its eyes and ears, the synapses of the mutant mice formed more rapidly compared with those of healthy mice, the scientists found.

 But by five weeks, when some synapses typically strengthen while others weaken in a normal process called pruning, the synapses had completely deteriorated in the mutant mice. In collaboration with another Duke researcher, Henry Yin, an assistant professor in psychology & neuroscience, the team also investigated the changes in synaptic function in these mutant mice and found severe alterations of the synaptic physiology.

Not only did the researchers see faulty circuits in the mice missing cortical Htt, they also saw signs of cellular stress in the brain, in the exact spot within the cortex that projects to the striatum, another brain area targeted by Huntington’s disease in people. “There’s something about that particular circuit that is vulnerable to changes in Htt,” Eroglu said.

The researchers also examined what happens in early brain development in a mouse model of Huntington’s disease. Similar to people with the disease, these animals have one normal copy of the Htt gene, and one mutated copy, which produces a protein that is present in cells but in expanded form.

The researchers found the same pattern: the Huntington’s disease model animals have synapses that initially mature much faster than normal in the cortex and then die off.

The new results also suggest that missing Htt for a prolonged period may not only affect the development but also the maintenance of healthy synapses, Eroglu said.

That’s especially relevant to a current strategy for treating Huntington’s disease: dialing down Htt levels in the brain using gene therapy or small-molecule inhibitors. But it has been a challenge to target the mutated copy of the gene, not the normal copy. Interested in the implications of lowering overall Htt levels, the group plans to delete Htt in the mouse brain later in life and measure the number of its synapses.

Other mouse models of the disease are also likely to have these faulty circuits. “We think this is probably a common thing, but that’s something we’re working on: whether we can detect early signs of faulty connections, correct it before the disease starts, and make these mice better,” Eroglu said.